For the determination of ions in solutions, use is frequently made of the potentiometric ion-selective electrode (Cammann, K., Die Arbeit mit Ionenselektiven Elektroden [Working with ion-selective electrodes], 2nd ed., Springer Verlag: Berlin, Heidelberg, New York, 1977). Ion-selective electrodes are electrochemical sensors with which the concentration or activity of specific ions can be determined by means of a potential difference. The ion-selective potential difference occurs at the phase boundary between active electrode material/electrolyte and depends according to the Nernst equation on the activity of a specific ion in the solution. One example of sensors of this type are ion-selective field-effect transistors (for example DE 29344005 C2).
An ion-selective membrane is the key component of all potentiometric ion sensors. It establishes the preference with which the sensor responds to the analyte in the presence of various interfering ions from the sample. If ions can penetrate the boundary between two phases, then an electrochemical equilibrium will be reached, in which different potentials in the two phases are formed. Originally, ion-selective electrodes used glass or crystalline membranes, across which only the selected species of ion could migrate or be exchanged. Later, electrodes based on liquid ion-exchangers, also known as liquid-membrane electrodes, were introduced.
In the latter, the ion-exchange solution is immobilized within a polymer or ceramic membrane. The main component of said electroactive membrane is a neutral or charged compound, which is able to complex ions reversibly and to transfer them through an organic membrane by carrier translocation. This compound is called an ionophore or an ion carrier. There are two kinds of ionophores: charged one and neutral carriers. They are mobile in both free and complexed forms, so the mobilities of all species are part of the selectivity coefficient together with ion-exchange equilibrium. The mobile binding sites are dissolved in a suitable solvent and usually trapped in a matrix of organic polymer (gel). Ion activity measurements are performed predominantly in aqueous media, so all membrane constituents are lipophilic. Therefore, the primary interaction between the ion in water and the lipophilic membrane containing the ionophore is the extraction process.
Ionselective electrodes (ISEs) for the determination of organic ions or ionizable organic molecules are typically composed of an ion pair consisting of the analyte to be determined and a lipophilic counterion (e.g. tetraphenylborate). Consequently as a general rule during ISE development for each analyte the ISE matrix compositions needs optimization by introducing a certain amount of plasticizer specific for the analyte to be determined. Hence there is no general ISE composition, let it be a generally applicable plasticizer for a wide range of organic ions or ionizable organic molecules, i.e. a composition that is applicable across different organic ions and ionisable organic molecules.
Typical polymeric membranes are based on plasticized poly(vinylchloride) (PVC) and contain approximately 66% of an plasticizer and 33% of PVC. Such a membrane is quite similar to liquid phase, because diffusion coefficients for dissolved low molecular weight ionophores are in the order of 10−7-10−8 cm2/s. An appropriate plasticizer is added to a membrane in order to ensure the mobility of the free and complexed ionophore. It determines the membrane polarity and provides suitable mechanical properties of the membrane. The ionophore is usually present in 1% amount (approximately 10−2M), which is relatively low as compared to the glass electrode. An ion selective membrane can contain a salt of lipophylic anion and hydrophylic cation (additive), which improves performances of a membrane. Although other polymers like: polisiloxane, polystyrene, PMMA, polyamide or polyimide can be used as a membrane matrix, PVC is the most widely used matrix due to simplicity of membrane preparation.
As a results of the introduction of natural as well synthetic ionophores in ion-selective membranes, ISEs for direct measurement of various cations and anions were designed, and ISEs have found a wide field of applications, e.g. in clinical chemistry, electrophysiology, as detectors in ion chromatography, in highly selective transport processes through artificial membranes (also biological membranes), etc. . . . .
There are however, a number of disadvantages associated with the traditional liquid-membrane electrodes. For example, it is known that exudation of plasticizer and leaching of dissolved ionophores may ultimately limit the lifetime of carrier-based electrodes. The former process may lead to mechanical instability and electrode failure. In an effort to address this problem, the present inventors recently developed a liquid-membrane electrode having a gradient of the ionophores towards the sample contact surface and a decreasing gradient of electrically conducting particles towards the sample contact surface (PCT Publication WO 2005/103664). Such an electrode with a gradient polymer was shown to be extremely mechanically robust and sensitive, and particularly useful in HPLC, Capillary Electrophoresis and pharmaceutical applications such as dissolution testing.
However, said gradient polymer membrane electrode doesn't address a further disadvantage of the current liquid-membrane electrodes. As already explained hereinbefore, liquid-membrane electrodes are lipophilic in nature and therefore, the primary interaction between the ion in water and the lipophilic membrane containing the ionophore is the extraction process by the ionophore. Consequently, the selectivity of the ISE is predominantly determined by the ionophore. These ionophores are chosen to obtain high selectivity for only one ion, and are incorporated during electrode production. Such predefined matrixes are for example described in US 2002115224, wherein the sensor dots comprise a polymeric matrix and one or more (bio)chemical recognitions moieties (see [0021] of said US publication; and in EP1965198 directed to an optical-chemical carbon-dioxide sensor, and characterized in that the matrix comprises a pH-sensitive dye which can form an anionic species and a metal cationic species to interact with CO2 in the sample to be analysed (see [0016] to [0019] of this European patent publication).
Another approach to obtain selectivity is the incorporation during sensor production of a lipophilic salt containing the analyte of interest, and to use a plastisizer optimized for that specific ion of interest. Using this approach only a few ions can be determined by pre defined electrodes where each ion requires a specific electrode. For practical and commercial reasons this methodology is inapplicable to the vast amount of organic ions an ionizable compounds. One way to come to an ISE universally applicable for a wide range of organic ions or ionizable organic molecules, is based on a post manufacturing conditioning of the ISE's as presented by Bohets et al. in PCT publication WO2011/110517.
However, when using this approach one departs from a predetermined matrix composition with no possibility to further optimize the membrane for a specific analyte. Consequently, using the base matrix composition as presented by Bohets et al. in WO2011/110517 only a limited applicability is encountered.
Electrodes constructed and conditioned according to Bohets et al. showed good results for lipophilic compounds such as Dapoxetine. However when used for less lipophilic compounds such as galantamine poor results were observed. In general, the performance of these electrodes is limited in high ionic background (0.1 M) and low pH, and for any practical purpose the usable range is limited to logP 2 (Logarithm of the octanol water partition) compounds.
It has accordingly been an object of the present invention to develop a base matrix electrode composition for use in the conditioning methodology of Bohets et al. (supra) that spans a very wide range of analytes to support a commercial viable universal ion selective electrode. It has thus been an objective of the present invention to realize a basic polymeric matrix, which can be conditioned and converted into an ion-selective polymeric matric sensitive to a wide range of analyst, using a post-manufacturing procedure.